brussels’update’ · fluids • chest:’nejm201,’myburgh,’finfer,’bellomo’ •...

Brussels Update

Ajay Raithatha May 2013

Introduc<on

•  March 19-‐22 2013 •  SMACC, ISICEM, ESICM •  5630 delegates, •  200+ invited speakers •  Angus, Kellum, Macintyre, GaLnoni, JL Vincent, Brochard, Finfer, Pellosi, Annane, Tibboul, Van den

Bergue, Polderman, Rubenfield, Mehta, Rhodes, Marik Rannieri, Mythen, Singer, Wenden Bellomo, Venkatesh, Hillman, Myburgh etc etc etc!!

•  Gold Hall lectures: DVD •  Key points from lectures a[ended •  CVS & Resp & Trachy: separate presenta<on •  Setpoint, PROSEVA, IVOIRE, Albios, Bases, Tracman

Content •  Seda<on •  Fluids •  Cardiac arrest •  Fungal Infec<on •  Renal •  Transfusion •  Liver •  Resp: Proseva and Tracman only •  Pancrea<<s

Seda<on – less is more •  Kress (NEJM) 2000: seda<on holds: MV LOS •  Kress (AmJRCCM) 2003: F/U trial: PTSD •  Grant (Lancet) 2008: Paired sedaGon & weaning protocol: 300 paGents: sedaGon, MV, mortality

•  Treggiari (CCM) 2009: Light vs. deep sedaGon (Ramsey) •  MV & LOS, PTSD (NS), improved cogni<on

•  Stram (Lancet) 2010: Protocol of no sedaGon in MV •  140 paGents, non-‐blinded, IntervenGon: Haloperidol + Morphine, Control: ConvenGonal with sedaGon holds

Seda<on •  Vent free days: 13.8 vs. 9.6 (P=0.019) •  ICU LOS: 13.1 vs. 22.8 (P=0.03) •  Hospital LOS 34 vs. 58 (P=0.0039) •  Accidental extuba<on: 13% vs. 10% (P=0.69)!! •  Delerium: 20% vs 7% (P=0.04). ? more diagnosed

•  18% seda<on in interven<on group (ITT)

Seda<on •  CCM 2013: clinical pracGce guidelines for pain, asthma and delerium: useful summary paper

•  ANZICS (Am J CCM) 2012: XS seda<on ≈ mortality •  EEG may not be accurate in ICU •  Affected by delirium and encephalopathy (80%) •  Wide variaGon in BIS esp. in Ramsey 5-‐6 •  Need for a technology that allows the pnt. who is oversedated to be idenGfied

Tim Walsh: Need for a device that predicts overseda<on not sleep: FEMG promoted

Responsiveness colour in relation to RASS score

based on fEMG activity (Red/Amber)

Muscle paralysisNormal sleepIllness associated coma

Liver failureHypoxic brain injuryTraumatic brain injurySevere metabolic encephalopathy

Drug-induced comaExcessive dosing of sedative drugsAccumulation of sedative drugs

Decreased levels of patient stimulation

Seda<on

•  α-‐2 agonists may have +ve effects on immunomodula<on of macrophage ac<vity

•  BDZ’s and GABA A agents impair immunomodula<on in mice models: survival (CCM 2012)

•  Study presented which analyzed BDZ’s in GP database of pneumonia:

•  Arer MV analysis BDZ use significant

Seda<on

•  MENDS (JAMA) 2007: dexmedetomidine vs. Loraz, 106 pa<ents, double-‐blind, randomised, 2 centres

•  dexmedetomidine seda<on was associated with significantly fewer days alive without delirium or coma and a lower overall incidence of coma.

•  12-‐month <me to death: 363 days in dex group vs 188 days in the lorazepam group (P = .48)

•  Loraz vs. Midaz vs. Dexmetomidine trial underway

Fluids!!!! •  Most studies now show volume equivalence = 1.2:1 •  Dose: Visep 70mls/kg, 6S 40mls/kg, Chest 5mls/kg •  Strong RRT signal from these trials

•  CRSTMAS: CCM 2012: •  196 pnts: 4 centres! •  6% 130/0.4 vs. saline, no algorithmn, cvp used •  Haem stability with lower volumes of colloid •  NO excess adverse effects •  NOT powered to detect mortality or RRT effect •  28 d follow up ? Too early: 22 d k-‐m separa<on in 6S

Fluids

•  6S Trial: Scandinavian, Perner NEJM 2012 •  6% (130/0.4) vs. Plasmalyte upto 33mls/kg/day •  798 pa<ents •  Death or dialysis dependency (dd) 51% vs. 43% (Plas) •  RR 1.17 (P=0.03), death effect: 1 long-‐term dd •  RRT: 22% (HES) vs. 16% (P=0.04) •  Arer MV analysis: bleeding higher in HES (NS) •  High level of pre-‐randomisa<on fluid, no strict protocol and likely conserva<ve ini<al resus

Fluids

•  CHEST: NEJM 201, Myburgh, Finfer, Bellomo •  Voluven vs. Saline, 7000 pnts, 90% powered

–  Elec<ve pa<ents included •  RIFLE F/L, head injuries, >1000mls pre-‐rand excluded •  Significantly less fluid in HES group •  Mortality: 18% vs. 17% (P=0.26) •  Sepsis (30%), RIFLE I (36%) equal in both groups •  RRT: HES 7% vs. 5.8% (P=0.04) •  RIFLE I HES< saline, RIFLE F HES > saline (both NS) •  More adverse events in HES group •  No evidence of HES benefit, cost

Fluids •  CRISTAL: Anane, Nancy France •  ICU pnts needing fluid resus: colloid (<30mls/kg) •  30 d mortality: P=0.32 •  90 d mortality, 34 vs. 31% P=0.04 •  Reduced mortality at 90d in colloid group •  Also faster stabilisa<on with colloid •  BASES: 130/0.4 vs. Ringers

–  241 pa<ents –  28d Mortality: 29% vs. 28% (NS) –  RRT (NS) –  LOS: Colloid be[er

Fluids

•  Con: Visep, 6S, Chest: No clear resus goals or monitoring of volume status

•  Chest/6S randomised arer stabilisa<on •  Chest used saline •  Need a trial of the ini<al (24 hours) phase in sepsis •  Likely hypervolaemia and destruc<on of glycocalyx •  Van Linden (Anaesth Anal) 2013: safety of starches MA

–  No deleterious effects: RRT –  mortality (benefit signal) –  No reason to abandon starches in peri-‐op period –  RCT of Colloids Vs Ringers underway

• 

Fluids •  BJA 2011: trauma pa<ents •  Be[er lactate clearance with colloids •  Starches 50-‐100x cost: •  FDA statement: ESICM: ICM 2012: •  Not to use HES in pa<ents with severe sepsis or risk of acute

kidney injury and suggest not to use 6% HES 130/0.4 or gela<n in these popula<ons.

•  Not to use colloids in pa<ents with head injury and not to administer gela<ns and HES in organ donors.

•  Not to use hyperonco<c solu<ons for fluid resuscita<on. •  Conclude any new colloid should be introduced into clinical

prac<ce only arer its pa<ent-‐important safety parameters are established

•  Subsequent ICS & NICE statements noted

Fluids: meta-‐analyses

Trial Group No. of trials/ pnts Mortality: (RR) RRT: (RR)

Ga[as (ICM) 2013 35 (10391) 1.08 1.25

Zarychanski (JAMA) 2013 38 (10880) 0.91 >>1.09**** 1.32

6S Group (BMJ) 2013 9 (3456) 1.04 1.36

Patel (ICM) 2013 6 (3033) 1.13 1.42

**** arer exclusion of Boldt data from sub-‐analyses

No substan<ve data to jus<fy gela<ns as alterna<ve

ALBIOS •  Early phase Rx: Albumin + Crystalloid vs. Crystalloid •  1818 pnts, 100 centres, randomised: 20% albumin

–  903 HAS -‐ 907 Crystalloid •  From day 2 to day 28 (or un<l ICU discharge, whichever

comes first), fluid will be administered as follows: •  Treated group: HAS 300mls 20% in 3 hrs + crystalloid ini<ally •  Treated group: albumin will be infused on a daily basis, aimed

to maintain its serum concentra<on equal or above 30 g/l if lower than 25 g/l, 300 ml of 20% of albumin solu<on If equal or higher than 25 g/l and below 30 g/l, 200 ml of 20% of albumin solu<on

•  If higher than or equal to 30 g/l, no albumin will be infused. Albumin solu<ons infused over a period of 3 hours.

•  Further infusion of crystalloids will be allowed •  No infusion of colloids, other than albumin

ALBIOS •  Used ‘Rivers’ resus protocol •  28 d and 90 d mortality as end points •  ‘I am only interested in the mortality’ •  2 subgroups of interven<on wrt <me – Within 6 hours of randomisa<on – Within 24 hours of randomisa<on

•  Provisional data: •  Less posi<ve fluid balance in albumin group •  Significant arer analysis

Albios •  ICU mortality: NS (28 day) •  41.1% vs. 43.6% (P=0.29) Early Group •  41.3% vs. 45% (P=0.20) Late Group •  90 day mortality (ini<al data only) •  42% vs. 48% : P = 0.03 •  4th SOFA: P= 0.04 •  Cost analysis: Survival: •  Gelofusin: 18,000 € •  Albumin: 18,000 € 0.118 •  HES: 36,000 € -‐0.118

My view: •  1) No colloid or gela<n in sepsis, though we s<ll await a true trial of early phase of resus

•  2) Hartman’s or saline (if Cl-‐ okay) •  3) Consider plasmalyte if raised K+/Lactate •  4) In sickest quar<le (APACHE >24): reasonable to give albumin if <20, ? When to stop. NOT in head injured, though Lund noted!

•  5) Periop/elec<ve: Colloid abandonment difficult to jus<fy wrt EBM, but based on cost and sugges<on of harm elsewhere……thoughts

Cooling and cardiac arrest •  Polderman’s: Passive rewarming likely too quick •  Avoidance of pyrexia crucial in avoiding HBI

•  Seizures: •  Very common post cardiac arrest •  EEG: guides treatment and aids prognos<ca<on •  Con<nuous EEG may improve survival and aid care •  Simplified EEG enough: 6 x subdural needles •  Phenytoin/ Keppra and Clonazepam best agents •  +/-‐ Thiopentone if Epilep<form

Neuro-‐prognos<ca<on arer cardiac arrest •  Prolonged recovery arer cooling for seda<ves to wear off:

recommend upto 5 days if propofol/Midaz •  Most signs remain very non-‐specific with high false+ve •  Absence or abnormal motor signs NOT useful •  Brainstem signs incl. pupil reflexes: lower false +ve •  EEG helpful, off seda<on at 48 hours post admission •  A reac<ve EEG good in predic<ng a good outcome even if

having seizures •  A non-‐reac<ve background predic<ve of poor outcome •  Preserved EEG background, Late seizures, Pupil reflexes

arer cooling suggest possibility of good outcome

Neuro-‐prognos<ca<on arer cardiac arrest

•  SSEP: •  Bilateral absent cor<cal responses = very bad sign •  Presence of responses is less useful: may s<ll not wake •  Bouves (Neurol) 2009: 43% preserved SSEP didn’t wake

•  EEG reac<vity more useful in predic<ng good outcome

•  Bouves (Annal Neurol) 2012: 399 pa<ents, assessed false posi<ve rates of tests: – Motor responses: high false +ve –  Pupil reac<vity: useful –  Absent SSEP: most useful in predic<ng bad outcome

Neuro-‐prognos<ca<on arer cardiac arrest

•  Collabora<on with neuromed recommended as rou<ne prac<ce

•  Propofol be[er than BDZ as seda<on •  Seda<on takes longer to wear off than thought •  AHA recommends wai<ng longer than 72 hours •  Use mul<-‐modal assessment •  If +ve signs eg pupils: you should wait >>>EEG/SSEP •  Interes<ng discussion in ques<ons re: cost & resource implica<ons

Fungal infec<on In ICU

•  ICM 2009: candida colonisa<on, 0 pa<ents at autopsy had candida pneumonia

•  Rical ICM 2012: associa<on between candida colonisa<on and VAP

•  Especially if in biofilms •  MulG-‐resistant bacteria in those colonised with candida was higher

•  Persisted afer MV analysis

Fungal infec<on

•  Diagnosis of aspergillus difficult •  ICM 2012: 23% of H1N1 got invasive aspergillosis and generally early in the process

•  Cor<costeroids important risk factor (not beneficial) •  Different species may be seen in 2 lungs thus high azole resistance: voriconazole has been first line

•  Haem pa<ents, COPD, Flu, Steroids at risk groups •  Environmentally acquired azole resistance in EU •  Strong mortality predictor, 60-‐90%, (2x candidiasis) •  Some papers promote dual therapy ie add ambisome

ICU Candidiasis •  2012-‐13: ESCMID guidelines: •  For candidaemia: Caspofungin A1, Voriconazole B1,

Fluconazole C1 and should be treated A2 •  1/3 of cases in ICU at day 1-‐2 then 2nd peak at day 7+ •  Fluconazole prophylaxis recommended (B1) if recent

abdominal surgery AND recurrent GI perfora<ons or anastomo<c leakages. Caspofungin = C2

•  American guidelines for prophylaxis: –  High risk pa<ents in units with high candidiasis (Fluconazole) –  Neutropenia (Fluconazole) –  Solid Organ Transplants (Ambisome)

Fungal Infec<on •  Predic<on rule: Ostrosky-‐Zeichner: •  Major risk factors: (1 of) •  CVP (D1 to D3) or Broad spectrum an<bio<cs (D1 to D3) •  and ≥2 of

–  TPN (D1 to D3), hemodialysis (D1 to D3), major surgery (D-‐7 to D0), pancrea<<s (D7 to D0), cor<costeroids (D-‐7 to D3), immunosuppressants (D-‐7 to D0)

•  Very high nega<ve predic<ve value, If score < 3

•  Need for an<fungal stewardship by expert •  Studies showed 1/3 had wrong ini<al an<fungal choice

fever, and empirical fluconazole treatment did not improve

outcome when compared with placebo [30].

Recommendations. Early treatment of presumed fungaemia is

presumably associated with higher survival rates, but the

optimal time point for initiating empiric antifungal treatment

remains undetermined. Due to lack of data, no recommenda-

tion can be given for choosing a specific drug for fever-dri-

ven therapy. In general, such choice should be based on local

epidemiology and drug–drug interactions in the individual

patient and should be made among the same drugs as rec-

ommended for candidaemia. Further recommendations are

given in Table 4.

Diagnosis-driven approach (pre-emptive)

We defined pre-emptive therapy as therapy triggered by

microbiological evidence of candidiasis without proof of inva-

sive fungal infection.

Evidence. Several studies have addressed diagnosis-driven ther-

apy on grounds of detecting (1,3)-b-D-glucan in serum or

plasma. In a study on 46 ICU patients without infection or with

confirmed bacterial or fungal infection, glucan test results (G-

test; Associates of Cape Cod, East Falmouth, MA, USA) corre-

lated with infection, but not with fungal infection. The authors

suggested using the test to rule out invasive fungal infection

[31]. This was the key finding in a study using the FungitellTM

TABLE 3. Recommendations on antifungal prophylaxis in ICU patients

Population Intention Intervention SoR QoE References Comment

Recent abdominal surgery AND recurrentgastrointestinal perforations oranastomotic leakages

To prevent intraabdominal Candida infection Fluconazole 400 mg/day B I [8] PlaceboN = 43

Caspofungin 70/50 mg/day C IIu [9] Single armN = 19

Critically ill surgical patients with anexpected length of ICU stay ‡3 day

To delay the time to fungal infection Fluconazole 400 mg/day C I [10] PlaceboN = 260

Ventilated for 48 h and expected to beventilated for another ‡72 h

To prevent invasive candidiasis/candidaemia Fluconazole 100 mg/day C I [162] PlaceboN = 204SDD used

Ventilated, hospitalized for ‡3 day, receivedantibiotics, CVC, and ‡1 of: parenteralnutrition, dialysis, major surgery,pancreatitis, systemic steroids,immunosuppression

To prevent invasive candidiasis/candidaemia Caspofungin 50 mg/day C IIa [5] PlaceboN = 186EORTC/MSGcriteria used

Surgical ICU patients To prevent invasive candidiasis/candidaemia Ketoconazole 200 mg/day D I [22] PlaceboN = 57

Critically ill patients with risk factors forinvasive candidiasis/candidaemia

To prevent invasive candidiasis/candidaemia Itraconazole 400 mg/day D I [21] OpenN = 147

Surgical ICU with catabolism To prevent invasive candidiasis/candidaemia Nystatin4 Mio IU/day

D I [20] PlaceboN = 46

SoR, Strength of recommendation; QoE, Quality of evidence; ICU, intensive care unit; CVC, central venous catheter; IU, international units.The table displays the published evidence; therefore, other available antifungal agents are not mentioned here.

TABLE 4. Recommendations on fever-driven and diagnosis-driven therapy of candidaemia and invasive candidiasis

Population Intention Intervention SoR QoE References

Adult ICU patients with fever despitebroad-spectrum antibiotics and APACHEII >16

To resolve fever Fluconazole 800 mg/day D I [30]

ICU patients persistently febrile, but withoutmicrobiological evidence

To reduce overall mortality Fluconazole or echinocandin C IIu [28][163][164][7][27]

ICU patients with candida isolated fromrespiratory secretions

To cure invasive candidiasis or candidaemia early Any antifungal D IIu [42]

ICU patients with positive (1,3)-b-D-glucantesta

To cure invasive candidiasis or candidaemia early Any antifungal C IIu [39][31][37][35][32][36][34][33]

Any patient with Candida isolated froma blood culture

To cure invasive candidiasis Antifungal treatment A II [46][47][48][49]

APACHE, acute physiology and chronic health evaluation.aThe (1,3)-b-D-glucan tests have low specificity and sensitivity with false-positive results in the presence of haemodialysis, other fungal or bacterial infection, wound gauze,albumin or immunoglobulin infusion.

22 Clinical Microbiology and Infection, Volume 18 Supplement 7, December 2012 CMI

ª2012 The Authors

Clinical Microbiology and Infection ª2012 European Society of Clinical Microbiology and Infectious Diseases, CMI, 18 (Suppl. 7), 19–37

the proportion of patients receiving which type of lipid-based

amphotericin B formulation.

The combination of amphotericin B deoxycholate and

fluconazole has been as effective as fluconazole monotherapy

in a randomized trial, but patients had an increased risk of

toxicity and no survival benefit [74]. A small study (N = 72)

comparing fluconazole with amphotericin B deoxycholate

and 5-flucytosine showed no difference in overall response

to treatment [75].

Recommendations. Targeted treatment of candidaemia with

echinocandins is strongly recommended. The recommenda-

tion for liposomal amphotericin B or voriconazole is less

stringent, and fluconazole is recommended with marginal

strength only, except for C. parapsilosis. For detailed recom-

mendations, refer to Table 5.

Duration of targeted treatment, step-down to oral treat-

ment and diagnostics in candidaemia

Evidence. The duration of treatment depends on the extent

of organ involvement. In a population without documented

organ involvement, treatment aims to clear the infection

and at the same time to avoid deep-organ involvement. This

can be achieved by treating for 14 days after the end of

candidaemia [82]. To determine the end of candidaemia, at

least one blood culture per day should be taken until cul-

ture results come back negative. Treatment can probably

be simplified by stepping down to oral fluconazole after

10 days of intravenous treatment, if the patient is stable,

tolerates the oral route and if the species is susceptible

[55,63,64].

The diagnostic procedures to detect organ involvement

comprise transoesophageal echocardiography, fundoscopy

and search for a thrombus. A recent observational study

found infectious endocarditis in 8.3% of patients with candi-

daemia; the majority of these patients had no well-estab-

lished risk factors, that is, vascular prosthesis or persistent

candidaemia [83].

Some prospective studies addressed ocular candidiasis as

complication of candidaemia. The diagnostic approach was

usually based on weekly eye examinations. Immunosuppres-

sion and repeatedly positive blood cultures are risk factors

TABLE 5. Recommendations on initial targeted treatment of candidaemia and invasive candidiasis in adult patients

Intervention SoR QoE References Comment

Anidulafungin 200/100 mg A I [64] Consider local epidemiology (Candida parapsilosis, Candida krusei), lessdrug–drug interactions than caspofungin

Caspofungin 70/50 mg A I [67][55][63]

Consider local epidemiology (C. parapsilosis)

Micafungin 100 mg A I [61][63]

Consider local epidemiology (C. parapsilosis), less drug–drug interactionsthan caspofungin, consider EMA warning label

Amphotericin B liposomal 3 mg/kg B I [61][62]

Similar efficacy as micafungin, higher renal toxicity than micafungin

Voriconazole 6/3 mg/kg/daya,b B I [43][78][77]

Limited spectrum compared to echinocandins, drug–drug interactions,limitation of IV formulation in renal impairment, consider therapeutic drugmonitoring

Fluconazole 400–800 mga C I [165][53][74][54][64][76][75][73][72]

Limited spectrum, inferiority to anidulafungin (especially in the subgroupwith high APACHE scores), may be better than echinocandins againstC. parapsilosis

Amphotericin B lipid complex 5 mg/kg C IIa [57][58]

Amphotericin B deoxycholate 0.7–1.0 mg/kg D I [50][51][165][53][54][55]

Substantial renal and infusion-related toxicity

Amphotericin B deoxycholate plus fluconazole D I [74] Efficacious, but increased risk of toxicity in ICU patientsNo survival benefit

Amphotericin B deoxycholate plus 5-fluorocytosine D II [75]Efungumab plus lipid-associated amphotericin B D II [166]Amphotericin B colloidal dispersion D IIa [60]Itraconazole D IIa [76]Posaconazole D III No reference found

EMA, European Medicines Agency.Comparative clinical trials did not prove a survival benefit of one treatment over another. Primary intention of treating candidaemia is clearing the blood stream.aNot all experts agreed, SoR results from a majority vote.bThe licensed maintenance dosing is 4 mg/kg/day.

CMI Cornely et al. Diagnosis and management of Candida diseases 2012 25

ª2012 The Authors

Clinical Microbiology and Infection ª2012 European Society of Clinical Microbiology and Infectious Diseases, CMI, 18 (Suppl. 7), 19–37

Renal •  Rinaldo Bellomo's " Concept of renal shun<ng” •  The kidneys are greedy organs. 20% cardiac output •  Shun<ng also occurs at the micro circulatory level •  Arteriovenous shun<ng can occur in the seLng of

increase or decrease in renal blood flow •  Increase renal blood flow does not always result in

increase oxygen delivery •  whether the renal vascular bed vasoconstricts or

vasodilates in sepsis is not known, such phenotype heterogeneity may explain why 50% of sep<c pa<ents develop AKI

Renal •  A good cardiac output also does not always translate to good

renal perfusion •  However, a reduc<on in renal blood flow has been associated

with increase renal vascular resistance (Prowle CCM 2012) •  "Blood pressure targets for the kidneys” •  MAP of 60mmHg may some<mes work such as in younger

pa<ents, pa<ents on CRRT •  Early RRT Vs. Driving MAP with vasopressor may be beneficial •  More is not necessarily always be[er as an increase in renal

blood flow may further compromise oxygen delivery to the medulla.

•  Precipitous fall in blood pressure may be more important that an absolute BP

Renal •  IVOIRE Study: 200 pnts. 35 vs. 70 mls/kg •  RIFLE I and above, sepsis, vasopressor •  Mortality 28/60/90 d: P= 0.94: Nega<ve Study •  Full paper awaited •  Bellomo ICM 2013: 115 pnts. 25 vs. 40 mls/kg •  MAP, Vasopressor with 40mls/kg •  Honore: Annals of Inten Care 2011: Review: •  35mls/kg should remain standard dose in sepGc AKI

If ba[le of dose is lost ie: >40mls/kg then…. 1)  Absorp<ve membranes

2)  Pore size

Renal: Absorp<ve membranes

•  Yumota (ther apher) 2011: Upstream sepsis mediators esp HMGB1 may be blocked by membranes

•  Hirasawa (blood purif & dial) 2012: AN69ST membrane –  Observa<onal study: suggests increased survival

•  Cruz (JAMA) 2012: Polymyxin Haemoperfusion + RRT Vs. Standard RRT: –  Vasopressor Mortality (32% vs. 55% but P=0.43) –  3 further studies underway including Euphrates

Renal: Absorp<ve membranes

•  5x Large nega<ve trials on dose •  AN69 can capture HMGB-‐1 •  AN69ST does need antocoag but ? less •  ? Role of polymyxin extracorporeal circuits

•  Most cytokines are on <ssues hence all of this is likely to be <p of iceberg only

Renal: Pore size

•  Cytokine clearance c CVVH poor, higher clearance with increased pore size 60-‐80 Kda (high cut-‐off membrane

•  Belloma (trial underway): concept that middle membrane sizes may promote cytokine clearance and should not lead to albumin loss

•  Cheap, easy to use, ? role in sepsis •  AKI, Sepsis, Vasopressor •  76 pnts, double-‐blind, APACHE 2 > 25 •  High cut-‐off Vs. Standard Membranes

Renal-‐ pore size

•  90d mortality results awaited •  be[er cytokine clearance & reduced vasopressor •  Albumin Loss

•  Molegero (CCM) 2006: high cut-‐off membrane + sepsis

•  vasopressorcytokines SOFA resolu<on

Renal: Modali<es

•  Bellomo 2001: CVVH Vs. IHD in sep<c shock: more haem stability

•  Visonneau (Lancet) 2006: CVVHDF vs. IHD in MODS •  Lins (Nephrol Dial) 2009: CVVH vs. IHD •  Both RCT’s: No survival advantage

•  SLED: prolonged dialysis at lower dose: very stable •  CCM 2012: 200 pnts SLED vs. CVVH: No difference •  Wu (Am J surg) 2010: SLED vs. CVVH: No difference •  However only small and few studies

Renal: modality

•  PICARD study (Kid Int) 2009: CRRT superior to IHD in removing fluid in overloaded AKI pa<ents

•  CVVH approx 2x cost of IHD •  SLED mean filter <me 19 hours, be[er with citrate

•  Bellomo (CCM) 2008: MA of modality: •  Be[er control of fluid balance and be[er haemodynamic stability with CRRT

Renal: modality

•  ATN & RENAL: No mortality benefit wrt dose •  Sepsis 63% and 49.5 % •  IVOIRE added to data in sep<c cohort •  MA also no signal of dose benefit •  Thus 35mls/kg seems appropriate target in sepsis ? 40-‐45mls/kg assuming 80% effec<ve

•  Note IVOIRE showed lower mortality vs. RENAL: 28d 39%: Likely due to earlier RRT in course on AKI

Renal-‐ modality

RRT Dependence @ RENAL ATN

Day 28 13.3% 45.2%

Day 60 24.6%

Day 90 5%

•  Big difference in recovery of renal func<on •  ATN group had 62% pre-‐randomisa<on RRT within

24 hours vs 0% in RENAL •  ATN group had RRT prescribed and amended by

nephrologists vs. Intensevists in RENAL •  BUT also modality differences

Renal -‐ modality

•  ATN vs. RENAL: •  total HD sessions: 4.8/pnt (ATN) vs. 0.2/pnt (RENAL) •  Hypothesis thus that IHD pa<ents less likely to recover renal func<on beyond RRT

•  Schneider (ICM) 2013: MA of modality •  3400 pnts, 2x in RRT dependence in IHD vs. CVVH •  Persisted arer MV analysis eg CKD status •  Also as ITT signal may be even stronger •  This was for any CRRT (HD/VVH/HDF) vs. IHD

Renal: Access •  Am J Kid Dis 2000: Op<mal catheter lengths: •  RIJ 12-‐15 cm, LIJ 15-‐20cm, Fem 19-‐24 cm •  Straight Catheters

•  Dugne 2012: 750 pnts Fem vs. IJ •  No difference in catheter free survival or infec<on

•  ++ recircula<on with Fem vs. IJ only reduced by fem catheter length of 25cm

Renal -‐ Access •  Type of catheter: •  PVC vs. Silicone (expensive): minimal good data •  Bellomo 2007: Lumen characteris<cs eg double barreled vs standard: No difference in filter survival

•  Tip characteris<cs: No effect on filter survival •  11 French 250-‐300mls/min •  14 French 450-‐500 mls/min •  Yon 2103: 4 % Citrate locks (expensive) vs. Heparin locks associated with line infec<ons and patency: BUT in long term catheters

Catheter Issues

•  Marik CCM 2012: earlier studies showed a lower risk of CRBSI when IJ Vs. Femoral, BUT recent studies show no difference in the rate of catheter-‐related bloodstream infec<ons between the three sites

•  Dugne 2012: 750 pnts Fem vs. IJ •  No difference in catheter free survival or infec<on •  KDIGO guidelines 2012: InternaGonal society of nephrology: Khwaja Nephron Clin Pract 2012: various recommendaGons on CRRT including wrt Catheter

1st choice RIJ 2nd choice Femoral

Renal -‐ an<coagula<on

•  US registry data suggests 19 hours filter life •  Citrate: 6 RCT’s and a MA (Zhang ICM 2013) suggest improved bleeding parameters and longer filter life

•  Trend toward possibly kidney and pa<ent survival •  Hetzel (Nephrol Dial trans) 2011: 176 pnts, 2nd largest study:

•  Lower bleeding and longer filter life 37 hours vs 26 hours with citrate though no survival benefit

•  Need for careful protocol and experienced nurses

Citrate An<coagula<on

•  Wu 2012 (Nephrol Dial) •  Metaanalysis: •  6 trials, 488 pa<ents •  Circuit survival (NS): mean 26 hours •  Bleeding: Reduced: RR 0.34, NNT: 6.67 •  Alkalosis: NS •  Hypocalcaemia: RR 3.51: though no adverse incidents in rela<on to low Ca2+

Renal: Filter life lecture •  John Prowle: Barts (Baxter) Nephrology intensevist •  Most important = consistent high blood flow •  Proper set-‐up and de-‐airing •  Bubble trap common source of cloLng •  Essen<al to have reliable nurse-‐medic communica<on •  More an<coagulant should NOT be first line, no evidence to empirically add prostacyclin to heparin

•  As some back flow pump flow is ≠ blood flow •  SC bad: future fistula and thrombosis •  LIJ consistent problema<c for flow

Renal: Filter life lecture •  Preferred site: RIJ/Fem/LIJ/LSC •  Consider LIJ CVP if expected RRT •  CVP and CVVH catheter in RIJ (vascath distal) •  Shallow vein approach: transverse USS •  Build up Pump flow first NOT once on •  Pressure drop early sign of filter failing •  Access pressures > 100 suggest catheter issue

Renal: Filter life lecture

•  5 mls/second check on inser<on

•  Step wise strategy: 1.  Ini<ally check catheter 2.  Increase blood pump speed monitoring FF% 3.  Low bleeding risk: op<mise heparin +/-‐ prostacyclin 4.  High bleeding risk: increase pre-‐dilu<on

Renal: Dose

•  ATN & RENAL: No mortality benefit wrt dose •  Sepsis 63% and 49.5 % •  IVOIRE added to data in sep<c cohort •  MA also no signal of dose benefit •  Thus 35mls/kg seems appropriate target in sepsis ? 40-‐45mls/kg assuming 80% effec<ve

•  20-‐25mls/kg in non-‐sep<c pa<ents

Dose of RRT

Renal: Dose •  IVOIRE Study: 35 vs. 70 mls/kg for 96 hours •  RIFLE I and above, sepsis, vasopressor •  Mortality 28/60/90 d: P= 0.94: Nega<ve Study •  Full paper awaited •  Bellomo ICM 2013: 115 pnts. 25 vs. 40 mls/kg •  MAP, Vasopressor with 40mls/kg •  Honore: Annals of Inten Care 2011: Review: •  35mls/kg should remain standard dose in sepGc AKI

IVOIRE

•  Prospec<ve MC-‐ORCT: 18 ITU;s (Fr, Bel, Neth) •  140 pnts recruited (sep<c shock + AKI < 24 hours): 2005-‐2010!

•  137 pnts analysed: •  Lower than expected mortality but no difference •  HVHF 37.9% Vs. SVHF 40.8% •  No significant secondary end points

IVOIRE •  NO evidence that HVHF (70ml/kg/hr) reduces mortality Vs LVHF (35ml/kg/hr)

•  Also no early improvement in haemodynamic profile or organ func<on with HVHF

•  Study stopped early as slow pa<ent accrual and lack of resources a/c authors

•  Note interim analysis revealed lower than expected mortality in all pa<ents thus planned study size (480) insufficiently powerful to prove survival effect (15% AR in 28d mortality)

IVOIRE

•  Largest Mul<centre RCT of sepsis and AKI •  Poten<al deleterious effects of HVHF increasingly presented: excess electrolyte loss, micronutrient loss and drug effects

•  30.4% enrollment over 5 years but noted in editorial that curves cross at > 1 point at 28d and long term follow-‐up. Conclusion that results can be considered defini<ve

Renal Dose •  Most sources suggest at least 10-‐15% loss in delivered vs. prescribed dose

•  Belloma, Cass NEJM 2009: •  Some observa<onal studies have figures for delivered dose as low as 68%

•  Also we use pre-‐dilu<on which may further reduce

•  RENAL trial used post-‐dilu<onal CVVHDF

Transfusion

•  Healthy body replaces 15-‐20mls/day, ICU blood leLng 30-‐70mls/day = 30% of transfusions

•  Labs may only use 1-‐2 mls •  TRICC 838 pnts, <7 vs 7-‐9: 28% vs. 31%: P=0.35 •  Post Hoc: < 55 age and APACHE <20: improved mortality with conserva<ve strategy

•  JAMA 93 Marik: older blood problems offloading oxygen: RECESS & ABLE underway to assess unit age

Transfusion •  Dellinger (CCM) 2013: SS guidelines: men<on use of Tx in

EGDT to target HCT 30% in pnts with low Scvo2 in first 6 hours, based on Rivers 2001 NEJM (263 pnts)

•  Marik: ‘I categorically do not believe rivers!’, raised lactate may not be a marker of oxygen debt that can be improved by blood as paradoxically esp old blood may hold onto oxygen –  Arise and Promise underway (Angus, Pi[sburgh lead)

•  Villanueva NEJM 2013: 921 pnts acute upper GI bleed –  survival at 6 weeks higher in the restric<ve-‐strategy group –  frequency of further bleeding and the frequency of adverse events were lower in the restric<ve group

Liver -‐ ALF

•  More likely to improve if NOT transplanted •  Age/Poor grar/ •  Time to Tx/ vasopressor •  affect outcome most in transplanted pa<ents

•  Fall in Ammonia is a good prognos<c sign, more so in ALF vs. AOCLF

•  MARS: no effect on outcome: bridge

Liver -‐ Cirrhosis •  Organ dysfuncGon in cirrhosis •  Cardiac: •  Diastolic dysfunc<on common c E/A •  Low CI correlated with poor outcome and Cr •  Liver transplant reverses cardiomyopathy •  QT prolonged commonly

•  Renal: •  Renal blood flow reduced through worsening Child -‐Pugh scores independent of MAP

•  Albumin & Terlipressin most effec<ve Mx in HRS

Hepatopulmonary Syndrome •  Triad of: –  Hypoxaemia –  Cirrhosis & portal hypertension –  Intrapulmonary vasodilata<on

•  Platypnea-‐Orthodeoxia •  Poor outcome: some may benefit from pentoxyfyline •  Gene<c Polymorphism seen •  Collinson (Liver Trans) 2002: refractory hypoxaemia, OLT treatment of choice, complete resolu<on >80%

•  Poor prognosis without OLT, usually Liver disease rather than respiratory failure

Cirrhosis -‐ seda<ves •  Child C 3/12 mortality = 51% •  Remifentanyl: ‘may be more sensible approach pharmacokine<cally, cau<on pharmacodynamics’

•  Propofol and Dexmetomidine good drugs •  BIS very useful in assessing seda<on in these pa<ents

•  CCM consensus mee<ng on delerium (AOCLD) 2012: –  Haloperidol = bad –  Olanzapine: NO good evidence –  Dexmetomidine good –  Transplanta<on works best!

CLD: When to transplant (Wendon) •  Use MELD (age >11) •  MELD = 3.78[Ln serum bilirubin (mg/dL)] + 11.2[Ln INR] + 9.57[Ln serum

crea<nine (mg/dL)] + 6.43

•  Weisner (2003): 3/12 mortality in hospitalised pnts: •  40 or more — 71.3% mortality •  30–39 — 52.6% mortality •  20–29 — 19.6% mortality •  10–19 — 6.0% mortality •  <9 — 1.9% mortality

•  When MELD >15, be[er survival with than w/o OLD •  Age & SOFA at 48 hours biggest predictors of outcome •  20% 1 year mortality

Alcoholic Hepa<<s •  Maddrey >32 ≈ 30 % 1 month mortality –  (4.6 x (PT test -‐ control))+ S.Bilirubin in mg/d

•  Several RCT’s >> MA Mathurin (Gut) 2011 •  15% improved survival c steroids if Maddrey +ve

•  Pentoxyfylline: ? prevent HRS, 1 good trial; benefit •  Pn�yl + Steroid vs. Steroid: no addi<onal benefit •  Steroids + NAC: P = 0.006 (1/12) BUT P = 0.66 (3/12)!

•  Mathan (NEJM) 2011: 71% 1 year survival in transplanted AoCLD (alcoholic hepaGGs)

•  11% drinking again at 1 year

Alcoholic Hepa<<s •  Use of Lille model to predict survival (www.lille.com) •  Bili change/baseline PT/Alb/Age/Cr >115 •  6/12 survival: •  Lille < 0.45 90% •  Lille > 0.45 26%

•  Assessment of non-‐responder to steroids at 7 days (lille score) is very predic<ve of outcome

•  MARS ineffec<ve in non-‐responders to steroids

Respiratory

•  Only brief •  DVD awaited •  Separate presenta<on

Proseva Trial

•  Guerin, NEJM June 2013 •  Mul<center, randomized trial in France (5) and Spain (1) •  Included pa<ents with early, severe ARDS •  "Early” : included to the trial within 36 hours of mee<ng

ARDS criteria •  "Severe" was defined as a PaO2:FiO2 ra<o < 150 mm Hg

(with FiO2 of at least 60%, PEEP 5 cm H20, and <dal volume of 6 mL/kg ideal weight)

•  12-‐24 hour "stabiliza<on" period to verify inclusion criteria prior to randomiza<on

•  Randomized: prone or supine posi<oning daily up to 28 d •  No commercial support

Proseva: Interven<on

•  Prone posi<oning was conducted for at least 16 consecu<ve hours per day in standard ICU beds.

•  The pa<ent's head was rotated every 2 hours •  Proning was stopped once the pa<ent met oxygena<on requirements while supine for at least four hours (PaO2:FiO2 ≥ 150 mm Hg with PEEP ≤ 10 and FiO2 ≤ 60%)

•  Adjustments to mechanical ven<la<on, weaning parameters, seda<on, and paraly<cs were

•  Of note, all ICUs included in the trial had been using this prone posi<oning protocol for more than 5 years

PROSEVA: results

•  Randomized 466 pa<ents (mean PaO2:FiO2 100 mm Hg) •  Most pa<ents had ARDS due to pneumonia (about 60%), and most

received vasopressors (73-‐83%), neuromuscular blockers (82-‐91%), and many received glucocor<coids (40-‐45%)

•  28-‐day all-‐cause mortality compared to supine reduced •  (16% vs 32.8%, HR 0.39, NNT 6, p<0.001) •  90-‐day mortality (23.6% vs. 41%, HR 0.44, NNT 6, p<0.001) •  Although those randomized to supine posi<oning may have been

slightly sicker at baseline (higher SOFA score), this mortality benefit was s<ll significant arer adjustments for baseline SOFA scores

•  On average, prone pa<ents received 4±4 prone sessions las<ng for 17±3 hours.

•  Proned for 73% of the <me spent on a ven<lator

Tracman

•  Young, JAMA 2013 •  2004-‐2011: 909 pa<ents, 72 centres •  Early: days 0-‐4, Late days 10+ •  Primary outcome: 30d mortality: ITT •  Received a trachy: Early: 91.9%, Late 44.9%!! •  30 d mortality: 30.8% vs. 31.5% (NS) •  2 yr Mortality: 51% vs. 53.7: (p=0.74) •  Median ICU LOS: 13 days vs 13.1 days (P=0.74) •  Trachy complica<ons 5.5% vs. 7.8%

Acute Pancrea<<s •  New classifica<on system: Atlanta 1992: imprac<cal •  New….’Revised Atlanta Score’ •  2 phases: Early & Late (week 1: clinical, Late morphological)

•  Severity: Mild, Moderate and Severe

•  Diagnosis: 2/3 of: abdo pain, Lipase >3, CT findings •  Moderate: 1 or more of: –  Transient organ failure –  Local complica<ons w/o persis<ng organ failure –  Exacerba<on of co-‐morbidi<es

Acute Pancrea<<s •  Severe: – Persistent organ failure for > 48 hours (modified marshall) or infected necrosis

– Usually have local complica<ons in addi<on – Diagnos<c associa<on with increased mortality –  Infected necrosis high mortality

•  Onset now classified from start of abdo pain

Pancrea<<s •  In the second phase, the disease either resolves (edematous

pancrea<<s w/o necrosis) or tends to stabilize (but not normalize) or progress and enter into a protracted course las<ng weeks to months related to necro<zing process

•  Late phase: morphologic CECT criteria to diagnose the specific type of acute pancrea<<s: acute inters<<al edematous pancrea<<s (IEP) or acute necro<zing pancrea<<s—

•  A. Presence/absence and site(s) of necrosis •  B. Evidence for the presence/absence of infec<on

SAP: Complica<ons

•  Now defined as:

•  Peripancrea<c fluid collec<on •  Acute necro<c collec<on •  Pancrea<c pseudocyst •  Walled off necrosis •  Peripancrea<c necrosis

SAP: Round Table (points) •  Late complica<ons (> 2weeks): –  Necrosis & infec<on –  Extrahepa<c infec<on –  Vascular thrombosis –  Bowel ischaemia & necrosis –  Fistula forma<on

•  Early decompression in IAP in SAP may be helpful in preven<ng early perfora<on

•  Early sphincterotomy if biliary pancrea<<s: beneficial

SAP: Round Table (points) •  Early surgery & infected necrosis: No survival benefit •  Many trials suggest mortality with conserva<ve Mx •  Necrosis in 5-‐15% of pancrea<<s •  40-‐70% become infected with 30% mortality

•  Prophylac<c Abx (Mero Vs. Placebo) –  No mortality advantage –  Increased resistance

•  Thus Abx only if presence or ? infected necrosis •  Early feeding as a ‘therapy’: less infected necrosis in addi<on to transloca<on & gut integrity

SAP: Round Table (points)

•  transloca<on with TPN vs. EN (P= 0.05) •  Besselink (Lancet) 2008: Probio<cs in SAP: •  increased mortality, bowel necrosis •  Several studies showing superiority of PCT vs. CRP for detec<ng infected SAP 73% vs. 37% sensi<vity

•  Voort 2010: good study suppor<ng wait and see technique wrt surgical interven<on

•  Percutaneous sampling vs. Necrosectomy:

brussels’update’ · fluids • chest:’nejm201,’myburgh,’finfer,’bellomo’ •...

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